Multicentric study of efficacy and safety of growth hormone use in growth hormone deficient children in India
http://www.100md.com
《美国医学杂志》
Medical Services and Product Development, LG Life Sciences India Pvt. Ltd., Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, India
Growth Hormone being very expensive in India data on use of recombinant human growth hormone (rhGH) is scarce. The authors studied the effect and safety of one year of therapy with rhGH on growth velocity and predicted final height in Indian patients with growth hormone deficiency (GHD). A multicentric, prospective, open trial with rhGH was performed on 15 patients. Patients received rhGH in a dose of 0.7 IU (0.23 mg)/Kg/week. The mean pretreatment height was 111.2cms {SD 12.4}, height velocity was 3.1 cms per year {1.2} and predicted height was 146.5 cms {10.4} at a mean age of 12.0 (2.8). At the end of therapy mean height was 123.4 {11.9}, height velocity was 12.1 cms per year {2.8} and the predicted height was 153.0 cm {9.4}. The increase in predicted height was thus 6.5cm (4.2). The increment in height velocity with growth hormone therapy was statistically significant (p value= 0.001). The present study shows that children with growth hormone deficiency in India also benefit from therapy with rhGH even when treatment is started late as compared to the published Western data and there is a potential for increased final height.
Keywords: Growth hormone; Height velocity; Growth hormone deficiency
Recombinant human growth hormone (rhGH) became available in 1981 for clinical trials and has been widely used in the world from 1985.[1] As there is no state funding or health insurance system in place in India very few patients can afford growth hormone therapy. As such published data on use of growth hormone is scarce excluding some anecdotal reports of cases treated with rhGH. Studies reported have often been retrospective studies done on small number of cases with varying dosages and route of administration.[2],[3] The aim of this study was to assess the efficacy and safety of one year of therapy with rhGH on growth velocity and predicted adult height in children with Growth hormone deficiency (GHD) using a standard protocol. Hence we report for the first time from India the results of a multicentric, prospective, open label trial where 15 children with GHD were treated with rhGH for a period of one year.
Materials and Methods
A prospective, open label trial with rhGH was performed at five centers in 15 GH naive children with Growth Hormone Deficiency (GHD). The medical ethics committee of all the participating hospitals approved the study and an informed consent was obtained from all parents. The diagnosis of GHD was made by two growth hormone provocation tests where in the growth hormone level of less than 7 ng/ml was taken as cut off or one growth hormone stimulation test together with the classic clinical features of growth hormone deficiency (i.e. midfacial crowding, central obesity, proportionate short stature, immature facies with protuberant eyes, depressed nasal bridge, hypoplasia of the mandible, crowded teeth and underdeveloped genitals in the male). All these children fulfilled the anthropometric diagnostic criteria for GHD including low growth velocity. A total of 11 males and 4 females (Mean Age-12years) were studied. The inclusion criteria were GH naive children between 3 to 15 years of age with height less than -2 standard deviation (SD), height velocity below 25th percentile, a ratio of bone age/ chronological age of less than 0.9, with open epiphyses on bone age X-rays. The patients were included if they were euthyroid or in case of hypothyroid patients only if they were controlled on medication.
Patients were excluded if they were growth hormone resistant, had any major systemic illness, had known hypersensitivity to study drug, and had active neoplasia or intracranial tumor. Height was recorded using a Child Growth Foundation Stadiometer to the accuracy of 1 mm, while weight was recorded on a Salter electronic scale to an accuracy of 100 grams. At enrollment height, weight, parents' height, previous height measurement, pre-existing conditions and concomitant medications were recorded. Presence of other pituitary hormone deficiencies was noted. A detailed physical examination was performed, an X-ray of the non dominant wrist and hand for bone age was taken and blood was drawn for a hemogram, fasting blood glucose, glycosylated hemoglobin, calcium, phosphorus, alkaline phosphatase, serum electrolytes, blood urea, serum creatinine, alanine amino transferase (ALT) , aspartate amino transferase (AST), free T4 and free T3, thyroid stimulating hormone (TSH) and insulin like growth factor 1 (IGF-1).
All patients received growth hormone in a dose of 0.7 IU (0.23 mg)/Kg/week given as seven divided doses as subcutaneous daily injection at night. Growth hormone was provided by LG lifesciences (Eutropin) as 4 IU vials. The 4 IU vial contains 1.33 mg of lyophilized recombinant rhGH protein and a separate vial contains 1 ml solvent for solution. The protein consists of 191 amino acid residues and is produced from genetically engineered yeast cells of the strain Saccharomyces cerevisiae.
All patients were asked to maintain a diary and missed doses; local and systemic reactions were recorded. Height and weight measurements were performed again at 6 months and at the end of one year of therapy. Blood investigations (as above) were repeated after one year of therapy i.e. at the end of the study. All fifteen patients completed the one-year study period. TW3 RUS method was used for calculating the bone age and predicted height of children based on their current age, height and RUS score.[4]
Data analysis was performed using Microsoft excel 2000 data analysis pack. Height, weight, height velocity, body mass index (BMI), mid parental height (MPH) and IGF-1 were expressed as standard deviation scores (Z scores).[5],[6],[7] Non-parametric tests were used for comparison of pre and post treatment parameters.
Results
A total of 15 patients (Males-11, Females-4) were studied. The mean age at the start of therapy was 12 years (range- 7-15 years). At the beginning and at the end of therapy, all patients' thyroid function, creatinine, hemoglobin, electrolytes, blood sugar, glycosylated hemoglobin, calcium, and liver function tests were in normal range [Table - 1]. The maximum mean stimulated Growth Hormone level was 0.71ng/ml. Two patients had multiple pituitary hormone deficiencies and had substitution therapy with thyroxine in a dose of 100microgram/m 2 for over a year while two patients were on anti-epileptic therapy. Two patients reported urticaria during the first month of therapy, which subsided without anti-allergy treatment, while headache was reported by two patients. No other local or systemic reactions possibly occurring due to growth hormone administration were noted. Two boys showed enlargement in the testicular volume from 3 to 5 ml during the course of the study. The pretreatment and post treatment auxological data is presented in [Table - 2] (mean [SD]) and [Figure - 1] while the height, weight, height velocity, BMI standard deviation scores (Z scores) as well as the predicted heights have been presented in [Table - 3]. The mean pretreatment height velocity was 3.1 cm/year, which improved to 12.1 cm/year on therapy with rhGH. Thus there was a statistically significant mean increase of 9.03cm/year in the height velocity (p=0.001). The mean increment in bone age was 1.4 years at the end of therapy. The differences between pretreatment and post treatment height Z score, height velocity Z score and height prediction were significant (p=0.001 for all). The mean pretreatment predicted height was 146.5 cms {10.4} and at the end of therapy it was 153.0 cm {9.4}. The mean increment in predicted adult height at the end of therapy was 6.5 cm (4.2).
Discussion
Growth hormone therapy has been shown to be effective in children with GH deficiency by several workers around the world and is a standard therapy for GHD for last couple of decades.[8] In India, due to economic reasons, the numbers of patients receiving this therapy are very small.[3] GH therapy should ideally be started at the earliest so that the impact on final height outcome is best achieved.[9],[10] In the present study the average age at beginning of treatment was 12 years, which is late as compared to other studies, due to delay in seeking medical help and lack of funds for diagnosis and therapy.
The authors administered seven injections per week of rhGH by subcutaneous route, in a dose 0.7 IU (0.23 mg)/Kg/week as a standard protocol to all patients. As has been observed in other studies, males outnumber females and the male to female ratio was 2.8:1.[11],[12] In the present study there was a mean improvement of 9.03cm/year in the height velocity. The pretreatment height velocity Z score was -3.76, which improved to +6.55 on therapy with rhGH [Figure - 2]. The differences between pre and post treatment height Z score, height velocity Z score and height prediction was significant (p=0.001 for all) and the mean improvement in predicted final height at the end of therapy was 6.5 cm. The prediction equation for height velocity by Lippe et al when applied to authors patients gave a mean prediction of 9.25cm but the actual growth achieved by our group was 12.1cm,[13] this could be because our patients were severely affected with average GH peak value of 0.71ng/ml. Although two boys showed enlargement in the testicular volume from 3 to 5 ml during the course of the study this was unlikely to have influenced the growth velocity because puberty growth spurt in boys usually corresponds with testicular volume of 10 ml or more.[14]
At the end of 1 year of study there was no significant change in the bone age advancement, BMI and weight. There was a rise in insulin like growth factor levels during therapy but this rise was not statistically significant. Growth hormone being a diabetogenic compound, a rise in blood glucose and HbA1c is a matter of concern especially in Indian children who are known to be insulin resistant and thus prone for glucose intolerance and diabetes.[15] In authors cohort no significant change in the HbA1c or fasting glucose parameters were observed. All other biochemical parameters remained within normal range through the study period. Alkaline phosphatase (an index of osteoblastic activity) rose from a mean of 443(179.8) to 551.4 (364.9) IU/l suggesting increased bone turnover although this difference was statistically insignificant.
In India the incidence of GHD is believed to be around 1 in 4000 to 1 in 10000 and there is little information about its genetic pattern. The classical phenotype described in the western literature with central fat deposition is relatively less marked in Indian children.[16] Indian children are also diagnosed and treated late and every year that the child goes without therapy the growth is further compromised and hence these children are severely affected at initiation of therapy.
The cost of Growth hormone in India is very high (between Rs. 200-400/unit or Rs. 600-1200/mg). Thus the yearly cost for a 30 Kg child would be around Rs 3,30,600/- while the national average per capita income is about Rs 21,140/ year making it unaffordable for most patients.[17]
Conclusions
Growth hormone was safe and effective in authors cohort. Even after one year of therapy there was significant improvement in predicted adult height although as shown by many Western studies the longer the GH therapy, better is the final height achieved. Considering the economic problems faced by their patients many patients may at the most be able to continue GH for a year or so. Their data shows that even a year's therapy may make a significant positive impact on the patient's final height
Acknowledgements
The authors thank Dr. Madhulika Kabra, Additional Prof., All India Institute of Medical Sciences, New Delhi, Dr. Mala Dharmalingam, Associate Prof., M.S. Ramaiah Medical College and Hospital, Bangalore, Ms Deepa Lokhandi and the nursing and pharmacy staff of the respective hospitals for their valuable assistance in successful completion of the study.
We would also like to extend our sincere gratitude to LG Life Sciences India for their generous supply of human growth hormone.
References
1.Flodh H. Update on clinical use and experience of somatonorm (somatrem). Acta Pediatr Scand 1987; 337 : 130-133. [PUBMED]
2.Menon PSN, Virmani A, Sethi AK. Biosynthetic Growth hormone Therapy in children with Growth Hormone eficiency: Experience at AIIMS, New Delhi. Indian J Pediatr 1991; 58 : 71-77.
3.Raghupathy P. Growth Hormone Deficieny:A Vellore Experience: 1986-1990. Indian J Pediatr 1991; 58 : 79-79. [PUBMED]
4.Tanner JM, Healy MJ, Goldstein H, Cameron N. Assesment of skeletal maturity and prediction of adult height (TW3 method). 3rd ed. London; WB Saunders; 2001.
5.Agarwal DK, Agarwal KN, Upadhyay SK, Mittal R, Prakash R, Rai S. Physical and sexual growth pattern of affluent Indian children from 5-18 years of age. Indian Pediatrics 1992; 29: 1203-1282. [PUBMED]
6.Dehiya RD, Bhartiya D, Kapadia C, Desai MP. Insulin Like Growth Factor-1, Insulin Like Growth Factor Binding Protein-3 and Acid Labile Subunit Levels in Healthy Children and Adolescents in Mumbai Suburbs. Indian Pediatrics 2000; 37: 990-997.
7.Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity: British children 1965. Arch Dis Child 1966; 41 : 454-471. [PUBMED]
8.Frasier SD. Human pituitary growth hormone (hGH) therapy in growth hormone deficiency. Endocrine Reviws 1983; 4: 155-156. [PUBMED]
9.Bundak R, Hindmarsh PC, Smith PJ, Brook CG. Long-term auxological effects of human growth hormone. J Pediatr 1988; 112 : 875-879. [PUBMED]
10.Ranke MB, Bierich JR. Long term treatment of hypopituitarism. In Ranke MB, Bierich JR, eds. Growth Hormone Deficiency . Baltimore; Urban and Schwarzenber; 1983.
11.Cowell CT, Dietsch S, Greenacre P. Growth Hormone therapy for 3 years: The OZGROW experience. J Peditr Child Health 1996; 32 : 86-93. [PUBMED]
12.Darendeliler F, Hindmarsh PC, Brook CG. Dose-response curves for treatment with biosynthetic human growth hormone. J Endocrinology 1990; 125: 311-316. [PUBMED]
13.Frasier D, Costin G, Lippe BM, Aceto T, Bunger PF. Dose response curve for human growth hormone. J Clin Endocrinology & Metabolism 1981; 53 : 1213-1217.
14.Hindmarsh PC, Brook CGD. Normal Growth and its Endocrine control. In Clinical Pediatric Endocrinology, 3rd edn. Ed. Brook CGD. London, Blackwell Science, 1995; 185-106.
15.Bavdekar A, Yajnik CS, Fall CH, Bapat S, Pandit AN, Deshpande V, Bhave S, Kellingray SD, Joglekar C. Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both Diabetes 1999; 48(12) : 2422-2429.
16.Desai MP, Colaco MP. Growth Hormone Deficiency and Insensitivity. In : Desai MP, Bhatia V, Menon PS, eds. Pediatric Endocrine Disorders . 1st ed. Hyderabadh; Orient Longman; 2001; 87-105.
17.Reserve Bank Of India. Handbook of Statistics on Indian Economy. Reserve Bank of India 2004.(Khadilkar VV, Khadilkar AV, Nandy M, Mas)
Growth Hormone being very expensive in India data on use of recombinant human growth hormone (rhGH) is scarce. The authors studied the effect and safety of one year of therapy with rhGH on growth velocity and predicted final height in Indian patients with growth hormone deficiency (GHD). A multicentric, prospective, open trial with rhGH was performed on 15 patients. Patients received rhGH in a dose of 0.7 IU (0.23 mg)/Kg/week. The mean pretreatment height was 111.2cms {SD 12.4}, height velocity was 3.1 cms per year {1.2} and predicted height was 146.5 cms {10.4} at a mean age of 12.0 (2.8). At the end of therapy mean height was 123.4 {11.9}, height velocity was 12.1 cms per year {2.8} and the predicted height was 153.0 cm {9.4}. The increase in predicted height was thus 6.5cm (4.2). The increment in height velocity with growth hormone therapy was statistically significant (p value= 0.001). The present study shows that children with growth hormone deficiency in India also benefit from therapy with rhGH even when treatment is started late as compared to the published Western data and there is a potential for increased final height.
Keywords: Growth hormone; Height velocity; Growth hormone deficiency
Recombinant human growth hormone (rhGH) became available in 1981 for clinical trials and has been widely used in the world from 1985.[1] As there is no state funding or health insurance system in place in India very few patients can afford growth hormone therapy. As such published data on use of growth hormone is scarce excluding some anecdotal reports of cases treated with rhGH. Studies reported have often been retrospective studies done on small number of cases with varying dosages and route of administration.[2],[3] The aim of this study was to assess the efficacy and safety of one year of therapy with rhGH on growth velocity and predicted adult height in children with Growth hormone deficiency (GHD) using a standard protocol. Hence we report for the first time from India the results of a multicentric, prospective, open label trial where 15 children with GHD were treated with rhGH for a period of one year.
Materials and Methods
A prospective, open label trial with rhGH was performed at five centers in 15 GH naive children with Growth Hormone Deficiency (GHD). The medical ethics committee of all the participating hospitals approved the study and an informed consent was obtained from all parents. The diagnosis of GHD was made by two growth hormone provocation tests where in the growth hormone level of less than 7 ng/ml was taken as cut off or one growth hormone stimulation test together with the classic clinical features of growth hormone deficiency (i.e. midfacial crowding, central obesity, proportionate short stature, immature facies with protuberant eyes, depressed nasal bridge, hypoplasia of the mandible, crowded teeth and underdeveloped genitals in the male). All these children fulfilled the anthropometric diagnostic criteria for GHD including low growth velocity. A total of 11 males and 4 females (Mean Age-12years) were studied. The inclusion criteria were GH naive children between 3 to 15 years of age with height less than -2 standard deviation (SD), height velocity below 25th percentile, a ratio of bone age/ chronological age of less than 0.9, with open epiphyses on bone age X-rays. The patients were included if they were euthyroid or in case of hypothyroid patients only if they were controlled on medication.
Patients were excluded if they were growth hormone resistant, had any major systemic illness, had known hypersensitivity to study drug, and had active neoplasia or intracranial tumor. Height was recorded using a Child Growth Foundation Stadiometer to the accuracy of 1 mm, while weight was recorded on a Salter electronic scale to an accuracy of 100 grams. At enrollment height, weight, parents' height, previous height measurement, pre-existing conditions and concomitant medications were recorded. Presence of other pituitary hormone deficiencies was noted. A detailed physical examination was performed, an X-ray of the non dominant wrist and hand for bone age was taken and blood was drawn for a hemogram, fasting blood glucose, glycosylated hemoglobin, calcium, phosphorus, alkaline phosphatase, serum electrolytes, blood urea, serum creatinine, alanine amino transferase (ALT) , aspartate amino transferase (AST), free T4 and free T3, thyroid stimulating hormone (TSH) and insulin like growth factor 1 (IGF-1).
All patients received growth hormone in a dose of 0.7 IU (0.23 mg)/Kg/week given as seven divided doses as subcutaneous daily injection at night. Growth hormone was provided by LG lifesciences (Eutropin) as 4 IU vials. The 4 IU vial contains 1.33 mg of lyophilized recombinant rhGH protein and a separate vial contains 1 ml solvent for solution. The protein consists of 191 amino acid residues and is produced from genetically engineered yeast cells of the strain Saccharomyces cerevisiae.
All patients were asked to maintain a diary and missed doses; local and systemic reactions were recorded. Height and weight measurements were performed again at 6 months and at the end of one year of therapy. Blood investigations (as above) were repeated after one year of therapy i.e. at the end of the study. All fifteen patients completed the one-year study period. TW3 RUS method was used for calculating the bone age and predicted height of children based on their current age, height and RUS score.[4]
Data analysis was performed using Microsoft excel 2000 data analysis pack. Height, weight, height velocity, body mass index (BMI), mid parental height (MPH) and IGF-1 were expressed as standard deviation scores (Z scores).[5],[6],[7] Non-parametric tests were used for comparison of pre and post treatment parameters.
Results
A total of 15 patients (Males-11, Females-4) were studied. The mean age at the start of therapy was 12 years (range- 7-15 years). At the beginning and at the end of therapy, all patients' thyroid function, creatinine, hemoglobin, electrolytes, blood sugar, glycosylated hemoglobin, calcium, and liver function tests were in normal range [Table - 1]. The maximum mean stimulated Growth Hormone level was 0.71ng/ml. Two patients had multiple pituitary hormone deficiencies and had substitution therapy with thyroxine in a dose of 100microgram/m 2 for over a year while two patients were on anti-epileptic therapy. Two patients reported urticaria during the first month of therapy, which subsided without anti-allergy treatment, while headache was reported by two patients. No other local or systemic reactions possibly occurring due to growth hormone administration were noted. Two boys showed enlargement in the testicular volume from 3 to 5 ml during the course of the study. The pretreatment and post treatment auxological data is presented in [Table - 2] (mean [SD]) and [Figure - 1] while the height, weight, height velocity, BMI standard deviation scores (Z scores) as well as the predicted heights have been presented in [Table - 3]. The mean pretreatment height velocity was 3.1 cm/year, which improved to 12.1 cm/year on therapy with rhGH. Thus there was a statistically significant mean increase of 9.03cm/year in the height velocity (p=0.001). The mean increment in bone age was 1.4 years at the end of therapy. The differences between pretreatment and post treatment height Z score, height velocity Z score and height prediction were significant (p=0.001 for all). The mean pretreatment predicted height was 146.5 cms {10.4} and at the end of therapy it was 153.0 cm {9.4}. The mean increment in predicted adult height at the end of therapy was 6.5 cm (4.2).
Discussion
Growth hormone therapy has been shown to be effective in children with GH deficiency by several workers around the world and is a standard therapy for GHD for last couple of decades.[8] In India, due to economic reasons, the numbers of patients receiving this therapy are very small.[3] GH therapy should ideally be started at the earliest so that the impact on final height outcome is best achieved.[9],[10] In the present study the average age at beginning of treatment was 12 years, which is late as compared to other studies, due to delay in seeking medical help and lack of funds for diagnosis and therapy.
The authors administered seven injections per week of rhGH by subcutaneous route, in a dose 0.7 IU (0.23 mg)/Kg/week as a standard protocol to all patients. As has been observed in other studies, males outnumber females and the male to female ratio was 2.8:1.[11],[12] In the present study there was a mean improvement of 9.03cm/year in the height velocity. The pretreatment height velocity Z score was -3.76, which improved to +6.55 on therapy with rhGH [Figure - 2]. The differences between pre and post treatment height Z score, height velocity Z score and height prediction was significant (p=0.001 for all) and the mean improvement in predicted final height at the end of therapy was 6.5 cm. The prediction equation for height velocity by Lippe et al when applied to authors patients gave a mean prediction of 9.25cm but the actual growth achieved by our group was 12.1cm,[13] this could be because our patients were severely affected with average GH peak value of 0.71ng/ml. Although two boys showed enlargement in the testicular volume from 3 to 5 ml during the course of the study this was unlikely to have influenced the growth velocity because puberty growth spurt in boys usually corresponds with testicular volume of 10 ml or more.[14]
At the end of 1 year of study there was no significant change in the bone age advancement, BMI and weight. There was a rise in insulin like growth factor levels during therapy but this rise was not statistically significant. Growth hormone being a diabetogenic compound, a rise in blood glucose and HbA1c is a matter of concern especially in Indian children who are known to be insulin resistant and thus prone for glucose intolerance and diabetes.[15] In authors cohort no significant change in the HbA1c or fasting glucose parameters were observed. All other biochemical parameters remained within normal range through the study period. Alkaline phosphatase (an index of osteoblastic activity) rose from a mean of 443(179.8) to 551.4 (364.9) IU/l suggesting increased bone turnover although this difference was statistically insignificant.
In India the incidence of GHD is believed to be around 1 in 4000 to 1 in 10000 and there is little information about its genetic pattern. The classical phenotype described in the western literature with central fat deposition is relatively less marked in Indian children.[16] Indian children are also diagnosed and treated late and every year that the child goes without therapy the growth is further compromised and hence these children are severely affected at initiation of therapy.
The cost of Growth hormone in India is very high (between Rs. 200-400/unit or Rs. 600-1200/mg). Thus the yearly cost for a 30 Kg child would be around Rs 3,30,600/- while the national average per capita income is about Rs 21,140/ year making it unaffordable for most patients.[17]
Conclusions
Growth hormone was safe and effective in authors cohort. Even after one year of therapy there was significant improvement in predicted adult height although as shown by many Western studies the longer the GH therapy, better is the final height achieved. Considering the economic problems faced by their patients many patients may at the most be able to continue GH for a year or so. Their data shows that even a year's therapy may make a significant positive impact on the patient's final height
Acknowledgements
The authors thank Dr. Madhulika Kabra, Additional Prof., All India Institute of Medical Sciences, New Delhi, Dr. Mala Dharmalingam, Associate Prof., M.S. Ramaiah Medical College and Hospital, Bangalore, Ms Deepa Lokhandi and the nursing and pharmacy staff of the respective hospitals for their valuable assistance in successful completion of the study.
We would also like to extend our sincere gratitude to LG Life Sciences India for their generous supply of human growth hormone.
References
1.Flodh H. Update on clinical use and experience of somatonorm (somatrem). Acta Pediatr Scand 1987; 337 : 130-133. [PUBMED]
2.Menon PSN, Virmani A, Sethi AK. Biosynthetic Growth hormone Therapy in children with Growth Hormone eficiency: Experience at AIIMS, New Delhi. Indian J Pediatr 1991; 58 : 71-77.
3.Raghupathy P. Growth Hormone Deficieny:A Vellore Experience: 1986-1990. Indian J Pediatr 1991; 58 : 79-79. [PUBMED]
4.Tanner JM, Healy MJ, Goldstein H, Cameron N. Assesment of skeletal maturity and prediction of adult height (TW3 method). 3rd ed. London; WB Saunders; 2001.
5.Agarwal DK, Agarwal KN, Upadhyay SK, Mittal R, Prakash R, Rai S. Physical and sexual growth pattern of affluent Indian children from 5-18 years of age. Indian Pediatrics 1992; 29: 1203-1282. [PUBMED]
6.Dehiya RD, Bhartiya D, Kapadia C, Desai MP. Insulin Like Growth Factor-1, Insulin Like Growth Factor Binding Protein-3 and Acid Labile Subunit Levels in Healthy Children and Adolescents in Mumbai Suburbs. Indian Pediatrics 2000; 37: 990-997.
7.Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity: British children 1965. Arch Dis Child 1966; 41 : 454-471. [PUBMED]
8.Frasier SD. Human pituitary growth hormone (hGH) therapy in growth hormone deficiency. Endocrine Reviws 1983; 4: 155-156. [PUBMED]
9.Bundak R, Hindmarsh PC, Smith PJ, Brook CG. Long-term auxological effects of human growth hormone. J Pediatr 1988; 112 : 875-879. [PUBMED]
10.Ranke MB, Bierich JR. Long term treatment of hypopituitarism. In Ranke MB, Bierich JR, eds. Growth Hormone Deficiency . Baltimore; Urban and Schwarzenber; 1983.
11.Cowell CT, Dietsch S, Greenacre P. Growth Hormone therapy for 3 years: The OZGROW experience. J Peditr Child Health 1996; 32 : 86-93. [PUBMED]
12.Darendeliler F, Hindmarsh PC, Brook CG. Dose-response curves for treatment with biosynthetic human growth hormone. J Endocrinology 1990; 125: 311-316. [PUBMED]
13.Frasier D, Costin G, Lippe BM, Aceto T, Bunger PF. Dose response curve for human growth hormone. J Clin Endocrinology & Metabolism 1981; 53 : 1213-1217.
14.Hindmarsh PC, Brook CGD. Normal Growth and its Endocrine control. In Clinical Pediatric Endocrinology, 3rd edn. Ed. Brook CGD. London, Blackwell Science, 1995; 185-106.
15.Bavdekar A, Yajnik CS, Fall CH, Bapat S, Pandit AN, Deshpande V, Bhave S, Kellingray SD, Joglekar C. Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both Diabetes 1999; 48(12) : 2422-2429.
16.Desai MP, Colaco MP. Growth Hormone Deficiency and Insensitivity. In : Desai MP, Bhatia V, Menon PS, eds. Pediatric Endocrine Disorders . 1st ed. Hyderabadh; Orient Longman; 2001; 87-105.
17.Reserve Bank Of India. Handbook of Statistics on Indian Economy. Reserve Bank of India 2004.(Khadilkar VV, Khadilkar AV, Nandy M, Mas)